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1. Field of the Invention
The present invention relates to weight loss. More particularly, the present invention relates to medication-aided weight loss treatments.
2. General Background of the Invention
Since treating patients for weight loss since 1981, the present inventor has observed that roughly seventy-five percent of his patients have little or absolutely no history of overweight or obesity prior to a major event associated with estrogen hormonal changes. The most common estrogen hormonal events are pregnancy (especially second and late pregnancies), hysterectomy, tubal ligation, or peri-menopause/menopause. Usually, the change is dramatic. Interestingly, these patients do not report a change in eating or exercise habits. Furthermore, exercise and strict weight loss produce only modest weight loss in many if not most of these patients, indicating that some aspect of fat metabolism has been altered as a result of the hormonal situations noted above. Because the genetic makeup of these patients has not changed, the present inventor has recognized the role of hormones in producing changes in body fat metabolism in humans.
These observations agree well with what is observed in the literature and current body of knowledge regarding hormones"" ability to elicit changes in body fat. Excess production of the hormone cortisol as seen in Cushing""s syndrome/disease produces significant truncal obesity which responds poorly if at all to weight loss. A similar situation results from prednisone and other steroid therapy in the human body. Adrenalectomy results in the absence of cortisol and an extreme loss of body fat. Even more significant to the present invention, patients who experience Polycystic Ovary Syndrome (PCOS) secrete huge amounts of the estrogen ESTRONE. Interestingly, these patients do not experience an increase in estrogenic side effects, but do exhibit extreme obesity, poorly responsive to diet and exercise. The role of hormones in eliciting obesity, at least in some, is not questioned. The special role of estrogens is strongly suggested by the inventor""s observations.
In U.S. Pat. No. 5,798,348, incorporated herein by reference, Dr. Maria Alemany has demonstrated that certain fatty acid monoesters of estrone are effective in eliciting weight loss and/or treating obesity. The use of fatty-acid monoesters of estrogens (FAME""s) for the treatment of obesity and/or overweight has been described wherein the fatty acid components are natural fatty acids designated specifically as the following fatty acids: oleic, linoleic, linolenic, stearic, palmitic palmitoleic, and arachidonic acids.
Oleoyl-estrone (OE) is a naturally occurring fatty acid monoester of estrogen (FAME-ES) that has been shown in numerous published articles to produce rapid and sustained weight loss in a variety of rats. Oleoyl-estrone is just one of a group of naturally occurring fatty acid monoesters of estrogen (FAME-ES). OE produces weight loss whether given via intravenous injection (i.v.), or orally, independent of leptin functionality. Rats given OE reduce their food intake in a dose related manner, while sustaining their energy output, thus resulting in significant and rapid weight loss. In one study, Zucker lean rats lost virtually all their lipid reserves, something that would not be achieved through starvation.
It has been demonstrated that by changing the fatty acid moiety on FAME-ES, the weight loss and appetite suppression effect of the molecule is greatly altered (Life Sciences, Vol. 62, No. 15, pp 1349-1359). To date, the most effective FAME-ES tested has been oleoyl-estrone. However, there are other FAME-ES compounds that have not been tested.
The present invention proposes a new solution to the above-mentioned problem by providing substantially pure new fatty-acid monoesters of estrogens and fatty acids, wherein:
a) the estrogen is selected from the group consisting of estrone, i.e.3-hydroxyestra-1,3,5(10)-trien-17-one; diethylstilbestrol, i.e.4,4xe2x80x2-(1,2-dietheyl-1,2-ethenediyl)-bisphenol; estrio, i.e. estra-1,3,5(10)riene-3,16,17-triol, and ethinylestradiol, i.e19-nor-17a-pregna-1,3,5(10)trine-20-yne-3,17-diol;
b) the fatty acid is a mono unsaturated fatty acid containing 20 carbons atoms or more, selected from the group consisting of eicosenoic, docosenoic acid and tetracosenoic acid, and
c) in a preferred embodiment, with the proviso that, when the estrogen is steroidal, the acyl group is attached to the hydroxyl group a the c-3 position of the steroid ring system.
In a preferred embodiment, the fatty-acid is eicosenoic acid. In a more preferred embodiment the estrogen is selected from the group consisting of estrone and diethylstilbestrol.
The present invention also provides a substantially pure fatty-acid monoester of an estrogen and a fatty acid, where the estrogen is either estrone, diethylstilbestrol, estriol or ethinyl estradiol; and the fatty acid is either eicosenoic acid, C-22 fatty acid, cis 13 docosenoic acid, or the C-24 fatty acid, cis 15 tetracosenoic.
In addition, the present invention also provides a substantially pure fatty-acid monoester of an estrogen combined with one fatty acid. This fatty acid can either be eicosenoic, docosenoic acid or tetracosenoic acid. Furthermore, the invention provides a substantially pure fatty-acid monoester consisting of estrone monoeicosenoate as well as a substantially pure fatty-acid monoester consisting of diethylstilbestrol monoeicosenoate. The invention also provides a substantially pure fatty-acid monoester where the estrogen is estrone and the fatty acid is cis 11 eicosenoic acid.
In addition, the present invention provides a pharmaceutical and/or cosmetic composition comprising a therapeutically and/or cosmetically effective amount of a substantially pure fatty-acid monoester of an estrogen and a fatty acid, in combination with at least one excipient acceptable for a predetermined administration. The estrogen can be estrone, diethylstilbestrol, estriol, estradiol and ethinyl estradiol and the fatty acid can be eicosenoic acid, the C-22 fatty acid, cis 13 docosenoic acid, and/or the C-24 fatty acid, cis 15 tetracosenoic acid. This pharmaceutical and/or cosmetic composition can be administered via intravenous injection, and the fatty-acid monoester can be integrated in a lipidic suspension. The lipidic suspension can be a lipoprotein suspension. This lipoprotein suspension can be a liposome suspension. Such liposome suspension can be obtained by addition of soy oil and egg phospholipids.
Furthermore, this invention provides a method of lowering body weight in a mammal by administering to the mammal an effective amount of a substantially pure fatty-acid monoester of an estrogen and a fatty acid. The estrogen can be estrone, diethylstilbestrol, estriol, estradiol and ethinyl estradiol, and the fatty acid can be eicosenoic acid, C-22 fatty acid, cis 13 docosenoic acid, or the C-24 fatty acid, cis 15 tetracosenoic acid, in combination with amounts of at least one member selected from the group consisting of pharmaceutically acceptable excipients and cosmetically acceptable excipients in an amount sufficient for the purposes thereof.
In addition, the present invention provides a substantially pure fatty-acid monoester of an estrogen and a fatty acid, wherein the estrogen is selected from the group consisting of estrone, diethylstilbestrol, estriol and ethinyl estradiol; the fatty acid is selected from the group consisting of eicosenoic acid, C-22 fatty acid, cis 13 docosenoic acid, and the C-24 fatty acid, cis 15 tetracosenoic acid, with the proviso that, when the estrogen is steroidal and has a steroid ring system with a C-3 position and a hydroxyl group at the C-3 position, the acyl group of the fatty acid is attached to the hydroxyl group at the C-3 position of the steroid ring system in the fatty acid monoester.
In another embodiment of the invention, molecules are synthesized by combining two different molecules. These molecules are referred to as synthesized combination molecules (SCM). The resulting synthesized combination molecule (SCM), when taken orally, elicits a decrease in appetite and food intake in mammals, while also producing a loss of body weight and/or body fat. These synthesized combination molecules are substantially pure combinations of:
a) a monounsaturated fatty acid molecule of 20 carbon atoms or more, and
b) a steroid.
The steroid and fatty acid are joined by an ester, ether, or amide linkage. Preferred fatty acids used in the SCM include the cis isomers of eicosenoic acid (20 carbon, monounsaturated), docosenoic acid (22 carbon, monounsaturated), and tetracosenoic acid (24 carbon, monounsaturated). Other monounsaturated fatty acids of greater than 20 carbons would also be effective. Preferred synthesized combination molecules (SCM""s) include the fatty acid monoesters in which the fatty acid is made up of eicosenoic acid, docosenoic acid, or tetracosenoic acid and joined via an ester bond to the steroid estrone. A particularly preferred SCM is the monoester of tetracosenoic acid and the steroid DHEA (dehydroepiandosterone).
In yet another embodiment, the invention provides synthesized combination molecules that are substantially pure combinations of:
1) a monounsaturated fatty acid molecule of 20 carbon atoms or more; and
2) a molecule containing a perhydrocyclopentanophenanthrene nucleus or a modification or derivative of a perhydrocyclopentanophenanthrene nucleus.
An example of a perhydrocyclopentanophenanthrene nucleus is a steroid. In one embodiment, the perhydrocyclopentanophenanthrene exists in the estrogen molecule. The fatty acid and perhydrocyclopentanophenanthrene are joined by an ester, ether, or amide linkage. Such combination molecules are effective in eliciting appetite suppression and a decrease in food intake in mammals, while also producing a loss of body weight and/or body fat. Perhydrocyclopentanophenanthrene is a saturated tetracyclic hydrocarbon, which is the precursor molecule of cholesterol and steroids. Perhydrocyclopentanophenanthrene is also the precursor of Vitamin D.
Suitable excipients include cornstarch, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sucrose.